Platform drug delivery system utilizing crystal engineering and theanine dissolution

ABSTRACT

A method of making a water-soluble doxorubicin-theanine cocrystal composition. The method includes the steps of providing a quantity of doxorubicin, adding a quantity of a theanine enantiomer to the quantity of doxorubicin to form a mixture of the quantity of doxorubicin and the enantiomer of theanine, wetting the mixture, and grinding the mixture for a length of time sufficient to produce a dried crystalline mass.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional of application Ser. No. 14/642,191, filed Mar. 9,2015, which is incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a platform drug delivery system and,more specifically, to a novel method of improving the delivery of lowsolubility pharmaceuticals utilizing crystal engineering and Theaninedissolution resulting in enhanced bioactivity, dissolution rate, andsolid state stability.

2. Background of the Invention

There are clear unmet needs in the pharmaceutical industry and medicalcommunity to improve drug delivery and improve the clinical status ofthe patient more rapidly. Therapeutic compounds are most stable in acrystalline form, but can display slow dissolution rates resulting inreduced bioavailability of the active pharmaceutical ingredient, therebyslowing absorption. The ongoing interest in modification of drugsubstances whose physical properties are less than desirable has led tosignificant study of issues associated with polymorphism andsolvatomorphism. More recently, it has been recognized that manysubstances may cocrystallize in a single continuous lattice structure,leading pharmaceutical scientists into new areas of crystal engineering.Cocrystals are mixed crystals where the cocrystal is a structurallyhomogeneous crystalline material that has been formed from discreteneutral molecular species that are solids at ambient temperatures.

Cocrystals represent novel forms of drug substances that would besuitable for incorporation in pharmaceutical solid dosage forms, andshould enable formulation scientists to overcome a variety of problemsthat are encountered during development of traditional formulations. Onecould consider cocrystals as being an alternative to polymorphs,solvatomorphs, and salts, and cocrystals represent a different approachto solve problems related to dissolution, crystallinity, hygroscopicity,etc. The most important improvement that might accompany the formationof a cocrystal would be an enhancement in the solubility of the drugsubstance, or at least a faster degree of dissolution.

The recently disclosed cocrystal system formed by aspirin(acetylsalicylic acid) and theanine (5-N-ethyl-glutamine) amplydemonstrates the potential advantages that can be achieved. Althoughseveral new pharmaceutical cocrystals have been advanced intopreclinical and clinical studies, further advances are needed to addressthe increasing complexity of new drug candidates. Unfortunately, it isnot yet possible to predict whether two substances will cocrystallize ornot, and therefore cocrystal screening studies are largely empirical innature.

The cocrystal of Theanine is a general form which can be translated toother ion containing drugs. This makes it very attractive to thepharmaceutical industry for the following reasons: drug companies wantto know that there are pipeline possibilities for other new products,creates a defensive measure for an existing branded pharmaceuticalagainst generic introduction, and expands indications for a lowsolubility branded pharmaceutical.

Crystallization and Theanine dissolution of low solubilitypharmaceuticals is paramount in the treatment of patients presentingwith a wide variety of emergent conditions where improved drug deliverywould be of benefit.

The harmful effect of glutamate upon the CNS were first observed in 1954by T. Hayashi, a Japanese scientist who noted that direct application ofglutamate to the CNS caused seizure activity (Wikipedia,“Excitotoxicity”. March, 2012.http://en.wikipedia.org/wiki/Excitotoxicity). Excitotoxicity is thepathological process by which nerve cells are damaged and killed byexcessive stimulation by neurotransmitters such as glutamate and similarsubstances. This occurs when receptors for the excitatoryneurotransmitter glutamate (glutamate receptors) such as the NMDAreceptor (N-methyl-D-aspartate receptor) and AMPA receptor(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) areoveractivated by glutamatergic storm (Wikipedia, “Excitotoxicity” March,2012 http://en.wikipedia.org/wiki/Excitotoxicity). Excitotoxins likeNMDA and kainic acid which bind to these receptors, as well aspathologically high levels of glutamate, can cause excitotoxicity byallowing high levels of calcium ions (Ca²⁺) to enter the cell (Manev,H.; Favaron, M.; Guidotti, A.; and Costa, E., Delayed increase of Ca²⁺influx elicited by glutamate: role in neuronal death. MolecularPharmacoloy. 1989 July; 36(1):106-112)). Ca²⁺ influx into cellsactivates a number of enzymes, including phospholipases, endonucleases,and proteases such as calpain. These enzymes go on to damage cellstructures such as components of the cytoskeleton, membrane, and DNA.Normally, glutamate concentration inside the cells is 10,000 timesgreater than outside the cell (Teichberg, Vivian., and Vikhanski, Luba.“Protecting the Brain from a Glutamate Storm.” The DANA Foundation.Thursday, May 10, 2007). Increased extracellular glutamate levels leadsto the activation of Ca²⁺ permeable NMDA receptors on myelin sheaths andoligodendrocytes, leaving oligodendrocytes susceptible to Ca²⁺ influxesand subsequent excitotoxicity (Nakamura et al, “S-nitrosylation of Drp1links excessive mitochondrial fission to neuronal injury inneurodegeneration” Mitochondrion, 2010 August; 10(5):573-8; Dutta et al.(January 2011). “Mechanisms of neuronal dysfunction and degeneration inmultiple sclerosis”. Prog Neurobiol 93 (1): 1-12). Excitotoxicity may beinvolved in spinal cord injury, stroke, traumatic brain injury, multiplesclerosis, Alzheimer's disease, Parkinson's disease, alcoholism, alcoholwithdrawal, over-rapid benzodiazepine withdrawal, and Huntington'sdisease (Wikipedia, “Excitotoxicity”. March, 2012.http://en.wikipedia.org/wiki/Excitotoxicity; Kim, A. H.; Kerchner, G.A.; and Choi, D. W., “Blocking Excitotoxicity or Glutamatergic Storm.”CNS Neuroprotection. Marcoux, Chap 1. Springer, New York. 2002. pp.3-36; Hughes, J. R., “Alcohol withdrawal seizures”. Epilepsy Behav 15(2): 92-7) (February 2009)). Toxicity from excess glutamate is alsothought to be a component of other conditions as diverse ashypoglycemia, damage to a newborns brain caused by interrupted oxygensupply during delivery, exposure to nerve gas, and is probably involvedin chronic nerve damage in such conditions as glaucoma, amyotrophiclateral sclerosis, and HIV dementia (Teichberg, Vivian, and Vikhanski,Luba. “Protecting the Brain from a Glutamate Storm.” The DANAFoundation. Thursday, May 10, 2007).

Theanine is extremely safe, with a LD₅₀ toxicity of >5000 mg/kg inhumans (“L-Theanine”. www.drugs.com/npp/I-theanine.html). Theanine mayprotect against nerve cell damage by blocking glutamine entrance tocells due to the similarity in stereochemical structures of Theanine andglutamine. (Kakuda T, et al., “Protective effect ofgamma-glutamylethylamide (Theanine) on ischemic delayed neuronal deathin gerbils,” Neuroscience Letters 2000; 289(3): 189-192). GABA(Gamma-Aminobutyric Acid) is the most widespread inhibitoryneurotransmitter of the brain. When GABA levels are decreased there isan augmentation of nerve impulses in the neuron. Theanine increases GABAlevels in the brain, opposing excess stimulation of nerve impulses byexcitatory neurotransmitters.

As such, crystal engineering and Theanine dissolution may be useful inthe prevention and treatment of diseases or conditions associated withglutamate toxicity, decreased glutathione levels, decreased GABA levels,neuronal damage or death from neurotransmitter excitotoxicity, amyloidbeta-induced neurotoxicity, neurotoxins and oxidative stress inducersthat damage the nervous system. Theanine crosses the blood-brain barriervia leucine-preferring transport system (Yokogoshi, Hidehiko; Kobayashi,Miki; Mochizuki, Mikiko; and Terashima, Takehiko, “Effect of Theanine,r-Glutamylethylamide, on Brain Monoamines and Striatal Dopamine Releasein Conscious Rats.” Neurochemical Research, May 1998, Volume 23, Issue5, pp. 667-673). The protective effect of L-Theanine againstaluminum-induced neurotoxicity was shown by Sumathi et al., 2014. Thestudy clearly indicates the potential of L-Theanine in counteracting thedamage inflicted by aluminum on rat brain regions (Sumathi, T.; Shobana,C.; Thangarajeswari, M.; Usha, R. “Protective effect of L-Theanineagainst aluminum-induced neurotoxicity in cerebral cortex, hippocampusand cerebellum of rat brain-histopathological, and biochemicalapproach.” Drug Chem Toxicol Mar. 24, 2014). Several environmentalneurotoxins and oxidative stress inducers are known to damage thenervous system and are considered major factors associated with theselective vulnerability of nigral dopaminergic neurons in Parkinson'sdisease (Cho, H. S.; Kim S.; Lee S. Y.; Park J. A.; Kim S. J.; Chun H.S.; “Protective effect of the green tea component, L-Theanine onenvironmental toxins-induced neuronal cell death.” Neurotoxicology. 2008July; 29(4):656-62). Cho et al., analyzed L-Theanine's capabilities toprotect DNA in cells from environmental toxins. The researchers used thehuman dopaminergic cell line SH-SY5Y, and subjected the cell line to theneurotoxins rotenone and dieldrin. There were a variety of benefitsfound in the cell cultures that were also treated or pre-treated withL-Theanine, namely, decreased DNA fragmentation and apoptotic celldeath. Yet, L-Theanine protected brain-derived neurotrophic factor(BDNF) and glial cell line-derived neurotrophic factor (GDNF) productionin the cells (Biohacks Blog, “L-Theanine Attenuates Beta-Amyloid PlaqueNeurotoxicity and Neuronal Cell Death.”). The authors claim thatL-Theanine directly provides neuroprotection against Parkinson'sdisease-related neurotoxicants and may be clinically useful forpreventing Parkinson's disease symptoms (Cho, H. S.; Kim S.; Lee S. Y.;Park J. A.; Kim S. J.; Chun H. S., “Protective effect of the green teacomponent, L-Theanine on environmental toxins-induced neuronal celldeath.” Neurotoxicology. 2008 July; 29(4):656-62). Di et al., showedthat L-Theanine protects the APP (Swedish Mutation) transgenic SH-SY5Ycell against glutamate-induced excitotoxicity via inhibition of the NMDAreceptor pathway (Di X., et al., “L-Theanine Projects The APP (SwedishMutation) Transgenic SH-SY5Y Cell Against Glutamate-InducedExitotoxicity via Inhibition of the NMDA Receptor Pathway.” Neuroscience168 (2010) 778-786). Memantine a glutamate antagonist, decreasesglutamate's effect by blocking the NMDA receptor. As well, presentinventor H. G. Brittain has shown that Memantine does form a cocrystalwith Theanine which may be useful in the prevention and treatment ofdiseases or conditions associated with glutamate toxicity. The presentinvention satisfies these and other medical needs and overcomesdeficiencies found in the prior art.

A new study that identifies the cause of Alzheimer's disease, dementia,and Parkinson's disease as the breakdown in function of the tau proteinin nerve cells and shows that a drug that is presently approved canreverse the memory loss associated with the diseases was reported in theOct. 31, 2014, edition of the journal Molecular Neurodegeneration(Hamaker, Paul. “New research points to tau protein malfunction as causeof Alzheimer's.” Nov. 2, 2004). This is the first time that research hasproven that the loss of tau protein function precedes the formation ofbeta-amyloid plaques in Alzheimer's disease. Dr. Charbel Moussa,professor of neuroscience at Georgetown University Medical Center, andcolleagues made the discovery (Hamaker, Paul. “New research points totau protein malfunction as cause of Alzheimer's.” Nov. 2, 2004). Celldeath is the result of the accumulation of nonfunctional tau protein andbeta-amyloid plaques in the nerve cells. The introduction of functionaltau protein into nerve cells that had a loss of tau protein restored thenormal nerve function. The discovery explains why some people can havebeta-amyloid plaques and suffer no memory loss or nerve damage (Hamaker,Paul. “New research points to tau protein malfunction as cause ofAlzheimer's.” Nov. 2, 2004). Nilotinib was found to assist in therestoration of nerve function in cells that had some tau protein in them(Hamaker, Paul. “New research points to tau protein malfunction as causeof Alzheimer's.” Nov. 2, 2004). The present invention satisfies theseand other medical needs and overcomes deficiencies found in the priorart.

Glutathione is the liver's first-line defense against drugs andchemicals. It is used by cancer cells against drugs and chemicals.Cancer cells use glutathione to detoxify doxorubicin and escort the drugout of cells. Theanine is able to interfere with this process due to itsstructural similarity to glutamate. Glutamic acid, or glutamate, is oneof the components of glutathione, the drug detoxifier. Because it lookslike glutamic acid, cancer cells take up and mistakenly use the Theanineto create glutathione. But the glutathione they create with Theaninedoes not detoxify like natural glutathione. Instead, this Theanine-basedglutathione appears to block the ability of cancer cells to detoxify.Further, in addition to enhancing doxorubicin's cancer-killing effectswithout harming healthy tissue, Theanine also keeps doxorubicin out ofhealthy tissue. This is a major added benefit, since one of thedrawbacks of the use of doxorubicin is its toxicity to the heart. Thepotential of Theanine as an adjunct to cancer chemotherapy was proposedby researcher Yasuyuki Sadzuka, who confirmed that Theanine, a majoramino acid in green tea, enhances the antitumor activity of doxorubicin(DOX) without an increase in DOX-induced side effects. He postulatedthat the action of Theanine is due to decreases in glutamate uptake viainhibition of the glutamate transporter and reduction of glutathione andDOX export from the cell. Theanine enhances the antitumor activity notonly of DOX but also of cisplatin and irinotecan. In essence, Sadzukafound that Theanine could block the export of doxorubicin (Adriamycin)from cancer cells by blocking the glutamate and glutathione transportermechanisms. The elevated level of the drug within cancer cells stronglyinhibits the tumor. (Sadzuka Y, et al., “The effects of Theanine, as anovel biochemical modulator, on the antitumor activity of Adriamycin.”Cancer Letters 1996; 105(2):203-209; Sadzuka Y, et al., “Modulation ofcancer chemotherapy by green tea.” Clinical Cancer Research 1998; 4(1):153-156; Sadzuka Y, et al., “Efficacies of tea components on doxorubicininduced antitumor activity and reversal of multidrug resistance.”Toxicology Letters 2000; 114(1-3): 155-162; Sadzuka Y, et al.,“Improvement of idarubicin induced antitumor activity and bone marrowsuppression by Theanine, a component of tea.” Cancer Letters 2000;158(2): 119-24; Sadzuka Y, et al., “Enhancement of the activity ofdoxorubicin by inhibition of glutamate transporter.” Toxicology Letters2001; 123(2-3): 159-67; Sadzuka Y, et al., “Effect of dihydrokainate onthe antitumor activity of doxorubicin.” Cancer Letters 2002; 179(2):157-163). The present invention satisfies these and other medical needsand overcomes deficiencies found in the prior art.

The box jellyfish (Chironex fleckeri) live primarily in coastal watersof northern Australia and throughout the Indo-Pacific. (Box Jellyfish,Box Jellyfish Pictures, Box Jellyfish Facts. National Geographic.1996-2014; Nation). Australian box jellyfish stings can cause acutecardiovascular collapse and death. Yanagihara and Shohet developedmethods to recover venom with high specific activity, and evaluated theeffects of both total venom and constituent porins at doses equivalentto lethal envenomation. Marked potassium release occurred within 5 minand hemolysis within 20 min in human red blood cells (RBC) exposed tovenom or purified venom porin. (Yanagihara, A. A.; Shohet, R. V.;“Cubozoan Venom-Induced Cardiovascular Collapse Is Caused byHyperkalemia and Prevented by Zinc Gluconate in Mice.” PLoS ONE, 2012; 7(12)). Electron microscopy revealed abundant, 12-nm transmembrane poresin RBC exposed to purified venom porins. C57BL/6 mice injected withvenom showed rapid decline in ejection fraction with progression toelectromechanical dissociation and electrocardiographic findingsconsistent with acute hyperkalemia. (Yanagihara, A. A.; Shohet, R. V.;“Cubozoan Venom-Induced Cardiovascular Collapse Is Caused byHyperkalemia and Prevented by Zinc Gluconate in Mice.” PLoS ONE, 2012; 7(12)). Recognizing that porin assembly can be inhibited by zinc,Yanagihara and Shohet found that zinc gluconate inhibited potassiumefflux from RBC exposed to total venom or purified porin, and prolongedsurvival time in mice following venom injection. These findings suggestthat hyperkalemia is the critical event following Chironex fleckerienvenomation and that rapid administration of zinc could be lifesavingin human sting victims. (Yanagihara, A. A.; Shohet, R. V.; “CubozoanVenom-Induced Cardiovascular Collapse Is Caused by Hyperkalemia andPrevented by Zinc Gluconate in Mice.” PLoS ONE, 2012; 7 (12)). Since thecurrent box jellyfish antivenom is not very effective, there is a clearunmet need in the medical community for a novel method of improving thedrug delivery of an intravenous zinc gluconate formulation utilizingcrystal engineering and Theanine dissolution. The present inventionsatisfies these and other medical needs and overcomes deficiencies foundin the prior art.

Malignant hyperthermia is a hypermetabolic disorder of skeletal musclethat is triggered in susceptible individuals (inherited as an autosomaldominant disorder) by several inhalation anesthetic agents (sevoflurane,desflurane, isoflurane, halothane, enflurane, and methoxyflurane) andsuccinylcholine. (Akif. “Malignant Hyperthermia.” Anesthesia General,Feb. 11, 2011). These anesthetic triggers cause intracellularhypercalcemia in skeletal muscle by decreasing the uptake of calcium bythe sarcoplasmic reticulum. The intracellular hypercalcemia activatesmetabolic pathways that result in adenosine triphosphate (ATP)depletion, acidosis, membrane destruction, and ultimately cell death.(Akif. “Malignant Hyperthermia.” Anesthesia General, Feb. 11, 2011).Core body temperature may reach as high as 112° F. Possiblecomplications of malignant hyperthermia includes amputation,rhabdomyolysis, compartment syndrome, disseminating intravascularcoagulation, arrhythmias, renal failure, metabolic acidosis, respiratoryacidosis, myopathy, and death. (Heller, J. L. “Malignant Hyperthermia.”Medline Plus, US National Library of Medicine, Apr. 5, 2013). Ifmalignant hyperthermia is not recognized and treated immediately duringsurgery, cardiac arrest may ensue. Dantrolene sodium which acts byinhibiting the release of calcium from the sarcoplasmic reticulum is theonly medication that is currently approved for the treatment ofmalignant hyperthermia. Application of a platform drug delivery systemutilizing crystal engineering and Theanine dissolution with Dantrolenesodium is paramount, since improved drug delivery would benefit thepatient and reduce or prevent the severe complications of thishypermetabolic disorder of skeletal muscle. The present inventionsatisfies these and other medical needs and overcomes deficiencies foundin the prior art.

The beneficial effects of the triptans in patients with migraine arerelated their multiple mechanisms of actions at sites implicated in thepathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilatedcerebral blood vessels, inhibition of the release of vasoactiveneuropeptides by trigeminal nerves, and inhibition of nociceptiveneurotransmission (Tepper, S. J.; Rapoport, A. M.; Sheftell, F. D.“Mechanisms of Action of the 5-HT 1B/1D Receptor Agonists.” Arch Neurol.2002 July; 59(7): 1084-8). Sumatriptan is indicated for the acutetreatment of migraine with or without aura in adults. It is known thatlarge doses of sumatriptan can cause sulfhemoglobinemia, a rarecondition in which the blood changes from red to greenish-black, due tothe integration of sulfur into the hemoglobin molecule (Patient BleedsDark Green Blood.” BBC News. Jun. 8, 2007). Serious cardiac events,including some that has been fatal, have occurred following the use ofsumatriptan tablets and have included ventricular tachycardia,ventricular fibrillation, coronary artery vasospasm, myocardialischemia, and myocardial infarction (Sumatriptan—FDA PrescribingInformation, Side Effects and Uses.” January 2014). Application of aplatform drug delivery system utilizing crystal engineering and Theaninedissolution with sumatriptan is paramount, since improved drug deliverywould improve the clinical status of the patient more rapidly, and wouldbe expected to reduce many serious side effects associated with the useof sumatriptan. The present invention satisfies these and other medicalneeds and overcomes deficiencies found in the prior art.

The various features of novelty which characterize the invention arepointed out with particularity in the claims annexed to and forming apart of this disclosure. For a better understanding of the invention,its operation advantages and specific objects attained by its uses,reference is made to the accompanying figures and descriptive matter inwhich a preferred embodiment of the invention is illustrated.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a methodutilizing crystallization and Theanine dissolution of low solubilitypharmaceuticals which is readily administrable to individuals through avariety of media.

Accordingly a platform drug delivery system and a method of improvingthe delivery of low solubility pharmaceuticals utilizing crystalengineering and Theanine dissolution resulting in enhanced bioactivity,dissolution rate, and solid state stability is disclosed.

It is an object of the present invention to provide a cocrystalcomposition composed of a quantity of a theanine enantiomer, and aquantity of a drug from a class selected from the group consisting ofnucleoside analog reverse transcriptase inhibitors, non-nucleosidereverse transcriptase inhibitors, non-purine selective xanthine oxidaseinhibitors, leukotriene receptor antagonists, beta-adrenergicagonists/alpha-adrenergic agonists, antihypertensive agents, loopdiuretics, thiazide diuretics, atypical antipsychotic/partial dopamineagonists, non-steroidal anti-inflammatory drugs, corticosteroids,antihistamines, antineoplastic agents, antibacterial agents,antibiotics, antiviral agents, antifungal agents, antiprotozoan agents,immediate dopamine precursor agent, catechol-o-methyltransferaseinhibitors, ergoline dopamine agonists, ergot derivative/dopamine D₂,D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2B), 5-HT_(2C), α_(2B) receptoragonists, antiparkinsonian agents, direct-acting skeletal musclerelaxants, noncompetitive N-methyl D-aspartate receptor antagonists,zinc salts of gluconic acid, serotonin-1 b and serotonin-1 d receptoragonists/antimigraine agents, cytomegalovirus nucleoside analog DNApolymerase inhibitors, and guanosine analogue antiviral agents.

In certain embodiments, the antihistimines are selected from the groupwhich includes ethanolamines and histamine H₁ receptor antagonists.

In further embodiments, the antineoplastic agents are selected from thegroup which includes protein tyrosine kinase inhibitors, antileukemicdrugs, topoisomerase 1 inhibitors, and anthracycline topoisomeraseinhibitors.

In yet further embodiments, the antibiotics are selected from the groupwhich includes cephalosporins, aminopenicillins, macrolides,sulfonamides, nitroimidazole antibiotics, fluorinated bistriazoleantibiotics, and cyclic lipopeptide antibiotics.

In certain embodiments, the direct-acting skeletal muscle relaxants arehydantoin derivatives.

It is also an object to provide a cocrystal composition which includes aquantity of a theanine enantiomer, and a quantity of a drug selectedfrom the group which includes lasix, aspirin, epinephrine, zincgluconate, dantrolene sodium, levodopa, entacapone, bromocriptine,cabergoline, nilotinib, memantine, ibuprofen, efavirenz, zidovudine,metronidazole, valganciclovir, fluconazole, ampicillin, erythromycin,sulfamethoxzole, cefdinir, cefadroxil, amoxicillin, daptomycin,acyclovir, febuxostat, hydrochlorothiazide, sumatriptan, prednisone,zinc gluconate, doxorubicin, irinotecan, aripiprazole, diflunisal,zafirulkast, and fexofenadine.

It is also an object to provide a cocrystal composition which includes aquantity of a theanine enantiomer, and a quantity of a drug for treatinga condition selected from the group which includes acute pulmonaryedema/congestive heart failure; acute myocardial infarction; acuteischemic stroke; acute allergic reactions, anaphylactic reactions frommedications, food, latex, insect bites/stings, cardiac arrest, acuteexacerbation of asthma, ventricular fibrillation, airway obstruction;Australian box jelly fish envenomations; neurologic emergenciesincluding, malignant hyperthermia, 3,4-methylenedioxymethamphetamineintoxication, serotonin syndrome, 2,4-dinitrophenol poisoning.

In certain embodiments, the theanine enantiomer is selected from thegroup which includes L-theanine, D-theanine, and DL-theanine.

In yet further embodiments, the theanine enantiomer is selected from thegroup which includes an alpha variant of theanine and a beta variant oftheanine.

In certain of these embodiments, the alpha variant of theanine isselected from the group which includes L-homotheanine, D-homotheanine,DL-homotheanine, L-bishomotheanine, D-bishomotheanine, andDL-bishomotheanine.

In certain other of these embodiments the alpha variant of theanine is ahomologous analog of theanine.

In certain other of these embodiments, the alpha variant of theaninecontains a functional group selected from the group which includeslinear, cyclic, or branched alkyl and derivatives thereof, linear,cyclic, or branched alkenyl and derivatives thereof, and aromaticradicals and derivatives thereof.

In some of these embodiments, the aromatic radicals are aryl radicals.

In further embodiments, the theanine enantiomer is a racemic mixture ofa beta variant of theanine containing a functional group selected fromthe group which includes linear, cyclic, or branched alkyl groups andderivatives thereof, linear, cyclic, or branched alkenyl groups andderivatives thereof, and aromatic radicals and derivatives thereof.

In certain other of these embodiments, the aromatic radicals are arylradicals.

In certain embodiments the theanine enantiomer is an S enantiomer of abeta variant of theanine containing a functional group selected from thegroup which includes linear, cyclic, or branched alkyl groups andderivatives thereof, linear, cyclic, or branched alkenyl groups andderivatives thereof, and aromatic radicals and derivatives thereof.

In further embodiments, the aromatic radicals are aryl radicals.

In yet further embodiments, the theanine enantiomer is an R enantiomerof a beta variant of theanine containing a functional group selectedfrom the group which includes linear, cyclic, or branched alkyl groupsand derivatives thereof, linear, cyclic, or branched alkenyl groups andderivatives thereof, and aromatic radicals and derivatives thereof.

In certain of these embodiments, the aromatic radicals are arylradicals.

In certain of these embodiments, the mixture further includes a sugaralcohol.

In certain of these embodiments, the sugar alcohol has a configurationselected from the group which includes the L-configuration and theD-configuration.

It is also an object to provide a cocrystal composition which includes aquantity of L-theanine, and a quantity of a chemical compositionselected from the group which includes acyclovir, amoxicillin,ampicillin, aripiprazole, bromocriptine, cabergoline, cefadroxil,cefdinir, dantrolene, daptomycin, diflunisal, doxorubicin, efavirenz,entacapone, epinephrine, erythromycin, febuxostat, fexofenadine,fluconazole, furosemide, hydrochlorothiazide, R-ibuprofen, irinotecan,levodopa, memantine, metronidazole, nilotinib, prednisone,sulfamethoxazole, sumitriptan, valganciclovir, zafirlukast, zidovudine,and gluconate-zinc.

During the development of the present invention, the ability of theanineto form cocrystal products with a wide variety of drug substances hasbeen evaluated. While theanine was not found to form cocrystals with 31drug substances (i.e., Acetaminophen, Acetazolamide, Amiodarone,Atorvastatin, Atropine, Carbamazepine, Celecoxib, Cisplatin, CoQ-10,Cyclosporine A, Dalbavancin, Dalmaprine, Desloratadine, Famotidine,Fenofibrate, Fingolimod, (RS)-Ibuprofen, Lamivudine, Linezolid,Mannitol, Moxifloxacin, (S)-Naproxen, Ondansetron, Oxcarbazepine,Pregabalin, Ramipril, Rosuvastatin, Rufinamide, Telmisartan,Venlafaxine, and Vilazodone), surprisingly theanine was found to formcocrystals with 34 drug substances (i.e., Acyclovir, Amoxicillin,Ampicillin, Aripiprazole, Bromocriptine, Cabergoline, Cefadroxil,Cefdinir, Dantrolene, Daptomycin, Diflunisal, Doxorubicin, Efavirenz,Entacapone, Epinephrine, Erythromycin, Febuxostat, Fexofenadine,Fluconazole, Furosemide, Gluconate zinc, Hydrochlorothiazide,(R)-Ibuprofen, Irinotecan, Levodopa, Memantine, Metronidazole,Nilotinib, Prednisone, Sulfamethoxazole, Sumitriptan, Valganciclovir,Zafirlukast, and Zidovudine).

Embodiments of the present invention are directed to a cocrystalcompositions including a quantity of a theanine enantiomer and drugsfrom the following drug classes: nucleoside analog reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors, non-purineselective xanthine oxidase inhibitors, leukotriene receptor antagonists,beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensiveagents, loop diuretics, thiazide diuretics, atypicalantipsychotic/partial dopamine agonists, non-steroidal anti-inflammatorydrugs, corticosteroids, antihistamines, antineoplastic agents,antibacterial agents, antibiotics, antiviral agents, antifungal agents,antiprotozoan agents, immediate dopamine precursor agent,catechol-o-methyltransferase inhibitors, ergoline dopamine agonists,ergot derivative/dopamine D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2B),5-HT_(2C), α_(2B) receptor agonists, antiparkinsonian agents,direct-acting skeletal muscle relaxants, noncompetitive N-methylD-aspartate receptor antagonists, zinc salts of gluconic acid,serotonin-1 b and serotonin-1 d receptor agonists/antimigraine agents,cytomegalovirus nucleoside analog DNA polymerase inhibitors andguanosine analogue antiviral agents.

In addition, embodiments of the present invention are directed tocompositions including a quantity of a theanine enantiomer and thefollowing drugs lasix, aspirin, epinephrine, zinc gluconate, dantrolenesodium, levodopa, entacapone, bromocriptine, cabergoline, nilotinib,memantine, ibuprofen, efavirenz, zidovudine, metronidazole,valganciclovir, fluconazole, ampicillin, erythromycin, sulfamethoxzole,cefdinir, cefadroxil, amoxicillin, daptomycin, acyclovir, febuxostat,hydrochlorothiazide, sumatriptan, prednisone, zinc gluconate,doxorubicin, irinotecan, aripiprazole, diflunisal, zafirulkast, andfexofenadine.

Embodiments of the present invention are also directed to compositionsincluding a quantity of a theanine enantiomer and drugs for treating thefollowing conditions: acute pulmonary edema/congestive heart failure;acute myocardial infarction; acute ischemic stroke; acute allergicreactions, anaphylactic reactions from medications, food, latex, insectbites/stings, cardiac arrest, acute exacerbation of asthma, ventricularfibrillation, airway obstruction; Australian box jelly fishenvenomations; neurologic emergencies including malignant hyperthermia,3,4-methylenedioxymethamphetamine intoxication, serotonin syndrome,2,4-dinitrophenol poisoning.

These and other non-limiting aspects and/or objects of the disclosureare more particularly described below. The various features of noveltywhich characterize the invention are pointed out with particularity inthe claims annexed hereto and forming a part of the disclosure. For abetter understanding of the invention, its operating advantages andspecific benefits attained by its uses, reference is made to theaccompanying drawings and descriptive matter in which exemplaryembodiments of the invention are illustrated.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings, which arepresented for the purposes of illustrating the exemplary embodimentsdisclosed herein and not for the purposes of limiting the same.

FIG. 1a is an x-ray powder diffraction pattern of theL-theanine/amoxicillin cocrystal;

FIG. 1b is an infrared absorption spectrum of the L-theanine/amoxicillincocrystal;

FIG. 2a is an x-ray powder diffraction pattern of theL-theanine/ampicillin cocrystal;

FIG. 2b is an infrared absorption spectrum of the L-theanine/ampicillincocrystal;

FIG. 3a is an x-ray powder diffraction pattern of theL-theanine/aripiprazole cocrystal;

FIG. 3b is an infrared absorption spectrum of theL-theanine/aripiprazole cocrystal;

FIG. 4a is an x-ray powder diffraction pattern of theL-theanine/bromocriptine cocrystal;

FIG. 4b is an infrared absorption spectrum of theL-theanine/bromocriptine cocrystal;

FIG. 5a is an x-ray powder diffraction pattern of theL-theanine/cabergoline cocrystal;

FIG. 5b is an infrared absorption spectrum of the L-theanine/cabergolinecocrystal;

FIG. 6a is an x-ray powder diffraction pattern of theL-theanine/cefadroxil cocrystal;

FIG. 6b is an infrared absorption spectrum of the L-theanine/cefadroxilcocrystal;

FIG. 7a is an x-ray powder diffraction pattern of theL-theanine/cefdinir cocrystal;

FIG. 7b is an infrared absorption spectrum of the L-theanine/cefdinircocrystal;

FIG. 8a is an x-ray powder diffraction pattern of theL-theanine/dantrolene cocrystal;

FIG. 8b is an infrared absorption spectrum of the L-theanine/dantrolenecocrystal;

FIG. 9a is an x-ray powder diffraction pattern of theL-theanine/daptomycin cocrystal;

FIG. 9b is an infrared absorption spectrum of the L-theanine/daptomycincocrystal;

FIG. 10a is an x-ray powder diffraction pattern of theL-theanine/diflunisal cocrystal;

FIG. 10b is an infrared absorption spectrum of the L-theanine/diflunisalcocrystal;

FIG. 11a is an x-ray powder diffraction pattern of theL-theanine/doxorubicin cocrystal;

FIG. 11b is an infrared absorption spectrum of theL-theanine/doxorubicin cocrystal;

FIG. 12a is an x-ray powder diffraction pattern of theL-theanine/efavirenz cocrystal;

FIG. 12b is an infrared absorption spectrum of the L-theanine/efavirenzcocrystal;

FIG. 13a is an x-ray powder diffraction pattern of theL-theanine/entacapone cocrystal;

FIG. 13b is an infrared absorption spectrum of the L-theanine/entacaponecocrystal;

FIG. 14a is an x-ray powder diffraction pattern of theL-theanine/epinephrine cocrystal;

FIG. 14b is an infrared absorption spectrum of theL-theanine/epinephrine cocrystal;

FIG. 15a is an x-ray powder diffraction pattern of theL-theanine/erythromycin cocrystal;

FIG. 15b is an infrared absorption spectrum of theL-theanine/erythromycin cocrystal;

FIG. 16a is an x-ray powder diffraction pattern of theL-theanine/febuxostat cocrystal;

FIG. 16b is an infrared absorption spectrum of the L-theanine/febuxostatcocrystal;

FIG. 17a is an x-ray powder diffraction pattern of theL-theanine/fexofenadine cocrystal;

FIG. 17b is an infrared absorption spectrum of theL-theanine/fexofenadine cocrystal;

FIG. 18a is an x-ray powder diffraction pattern of theL-theanine/fluconazole cocrystal;

FIG. 18b is an infrared absorption spectrum of theL-theanine/fluconazole cocrystal;

FIG. 19a is an x-ray powder diffraction pattern of theL-theanine/furosemide cocrystal;

FIG. 19b is an infrared absorption spectrum of the L-theanine/furosemidecocrystal;

FIG. 20a is an x-ray powder diffraction pattern of theL-theanine/hydrochlorothiazide cocrystal;

FIG. 20b is an infrared absorption spectrum of theL-theanine/hydrochlorothiazide cocrystal;

FIG. 21a is an x-ray powder diffraction pattern of theL-theanine/R-ibuprofen cocrystal;

FIG. 21b is an infrared absorption spectrum of theL-theanine/R-ibuprofen cocrystal;

FIG. 22a is an x-ray powder diffraction pattern of theL-theanine/irinotecan cocrystal;

FIG. 22b is an infrared absorption spectrum of the L-theanine/irinotecancocrystal;

FIG. 23a is an x-ray powder diffraction pattern of theL-theanine/levodopa cocrystal;

FIG. 23b is an infrared absorption spectrum of the L-theanine/levodopacocrystal;

FIG. 24a is an x-ray powder diffraction pattern of theL-theanine/memantine cocrystal;

FIG. 24b is an infrared absorption spectrum of the L-theanine/memantinecocrystal;

FIG. 25a is an x-ray powder diffraction pattern of theL-theanine/metronidazole cocrystal;

FIG. 25b is an infrared absorption spectrum of theL-theanine/metronidazole cocrystal;

FIG. 26a is an x-ray powder diffraction pattern of theL-theanine/nilotinib cocrystal;

FIG. 26b is an infrared absorption spectrum of the L-theanine/nilotinibcocrystal;

FIG. 27a is an x-ray powder diffraction pattern of theL-theanine/prednisone cocrystal;

FIG. 27b is an infrared absorption spectrum of the L-theanine/prednisonecocrystal;

FIG. 28a is an x-ray powder diffraction pattern of theL-theanine/sulfamethoxazole amoxicillin cocrystal;

FIG. 28b is an infrared absorption spectrum of theL-theanine/sulfamethoxazole cocrystal;

FIG. 29a is an x-ray powder diffraction pattern of theL-theanine/sumitriptan cocrystal;

FIG. 29b is an infrared absorption spectrum of theL-theanine/sumitriptan cocrystal;

FIG. 30a is an x-ray powder diffraction pattern of theL-theanine/valganciclovir cocrystal;

FIG. 30b is an infrared absorption spectrum of theL-theanine/valganciclovir cocrystal;

FIG. 31a is an x-ray powder diffraction pattern of theL-theanine/zafirlukast cocrystal;

FIG. 31b is an infrared absorption spectrum of theL-theanine/zafirlukast cocrystal;

FIG. 32a is an x-ray powder diffraction pattern of theL-theanine/zidovudine cocrystal;

FIG. 32b is an infrared absorption spectrum of the L-theanine/zidovudinecocrystal;

FIG. 33a is an x-ray powder diffraction pattern of theL-theanine/gluconate-zinc cocrystal;

FIG. 33b is an infrared absorption spectrum of theL-theanine/gluconate-zinc cocrystal;

FIG. 34a is an x-ray powder diffraction pattern of theL-theanine/acyclovir cocrystal; and

FIG. 34b is an infrared absorption spectrum of the L-theanine/acyclovircocrystal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Embodiments of the present invention employ Theanine (5-N-ethylglutamine) a non-protein amino acid found naturally in green tea leaves.

Embodiments of the present invention include cocrystallization oflow-solubility medication groups with Theanine (5-N-ethyl-glutamine).

Embodiments of the present invention include cocrystallization of thefollowing medication groups with theanine (5-N-ethyl-glutamine):nucleoside analog reverse transcriptase inhibitors, non-nucleosidereverse transcriptase inhibitors, non-purine selective xanthine oxidaseinhibitors, leukotriene receptor antagonists, beta-adrenergicagonists/alpha-adrenergic agonists, antihypertensive agents, loopdiuretics, thiazide diuretics, atypical antipsychotic/partial dopamineagonists, non-steroidal anti-inflammatory drugs, corticosteroids,antihistamines (ethanolamines, histamine H1 receptor antagonists),antineoplastic agents (protein tyrosine kinase inhibitors/antileukemicdrugs, topoisomerase 1 inhibitors, anthracycline topoisomeraseinhibitors), antibacterial agents/antibiotics (cephalosporins,aminopenicillins, macrolides, sulfonamides, nitroimidazole antibiotics,fluorinated bistriazole antibiotics, cyclic lipopeptide antibiotics),antiviral agents, antifungal agents, antiprotozoan agents, immediatedopamine precursor agent, catechol-o-methyltransferase inhibitors,ergoline dopamine agonists, ergot derivative/dopamine D₂, D₃, D₄,5-HT_(1A), 5-HT_(2A), 5-HT_(2B), 5-HT_(2C), α_(2B) receptor agonists,antiparkinsonian agents, direct-acting skeletal muscle relaxants(hydantoin derivatives), noncompetitive NMDA (N-methyl D-aspartatereceptor) antagonists, zinc salts of gluconic acid, serotonin-1 b andserotonin-1d receptor agonists/antimigraine agents, cytomegalovirusnucleoside analog DNA polymerase inhibitors and guanosine analogueantiviral agents.

The present invention is directed to, among other things,crystallization and theanine dissolution of medications from thefollowing drug classes: nucleoside analog reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors, non-purineselective xanthine oxidase inhibitors, leukotriene receptor antagonists,beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensiveagents, loop diuretics, thiazide diuretics, atypicalantipsychotic/partial dopamine agonists, non-steroidal anti-inflammatorydrugs, corticosteroids, antihistamines (ethanolamines, histamine H1receptor antagonists), antineoplastic agents (protein tyrosine kinaseinhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracyclinetopoisomerase inhibitors), antibacterial agents/antibiotics(cephalosporins, aminopenicillins, macrolides, sulfonamides,nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cycliclipopeptide antibiotics), antiviral agents, antifungal agents,antiprotozoan agents, immediate dopamine precursor agent,catechol-o-methyltransferase inhibitors, ergoline dopamine agonists,ergot derivative/dopamine D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2B),5-HT_(2C), α_(2B) receptor agonists, antiparkinsonian agents,direct-acting skeletal muscle relaxants (hydantoin derivatives),noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zincsalts of gluconic acid, serotonin-1b and serotonin-1d receptoragonists/antimigraine agents, cytomegalovirus nucleoside analog DNApolymerase inhibitors and guanosine analogue antiviral agents.

Further, the Theanine contained in compositions according to embodimentsof the present invention may be of any of L-form, D-form, DL-form.

According to embodiments of the present invention the L-, D-, DL-alphaamino acids of Theanine and their side-chain carbon homologues (nor,homo, and bishomologues) may have a functional R-group, where R1 maycontain linear, cyclic, or branched alkyl groups and derivativesthereof; linear, cyclic, or branched alkenyl groups and derivativesthereof; and aromatic radicals and derivatives thereof. In embodimentsof the present invention, the aromatic radicals may be aryl radicals.

According to the embodiments of the present invention in addition toL-Theanine, other analogues include D-Theanine, racemic Theanine or D,L-Theanine and its congeners including beta and reverse beta amino acidforms, shortened or nor-Theanine (aspartic acid analogue), and thelengthened homo-Theanines and their isomers. Further, gamma alkylamidoanalogues extend a full range of molecular property for drug cocrystals.

According to the embodiments of the present invention the singleenantiomers (S and R) and racemic forms (S, R-mixture) of the beta aminoacids of Theanine may have a functional R-group, where R1 may containlinear, cyclic, or branched alkyl groups and derivatives thereof;linear, cyclic, or branched alkenyl groups and derivatives thereof; andaromatic radicals and derivatives thereof. In embodiments of the presentinvention, the aromatic radicals may be aryl radicals.

Embodiments of the present invention may include cocrystal compositionsof drugs from the classes listed below and the enantiomers, L- andD-isomers, D, L-racemic mixture, S- and R-isomers, S, R-racemicmixtures, all rotamers, tautomers, salt forms, and hydrates of the alphaand beta amino acids of Theanine in which the N-substituted functionalR1-group [C4 or gamma-CH2-C(O)—NR1] may contain linear, cyclic, orbranched alkyl groups and derivatives thereof; linear, cyclic orbranched alkenyl groups and derivatives thereof; and aromatic radicals(which may be aryl radicals) and derivatives thereof making up all theanalogue forms of Theanine: nucleoside analog reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors, non-purineselective xanthine oxidase inhibitors, leukotriene receptor antagonists,beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensiveagents, loop diuretics, thiazide diuretics, atypicalantipsychotic/partial dopamine agonists, non-steroidal anti-inflammatorydrugs, corticosteroids, antihistamines (ethanolamines, histamine H1receptor antagonists), antineoplastic agents (protein tyrosine kinaseinhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracyclinetopoisomerase inhibitors), antibacterial agents/antibiotics(cephalosporins, aminopenicillins, macrolides, sulfonamides,nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cycliclipopeptide antibiotics), antiviral agents, antifungal agents,antiprotozoan agents, immediate dopamine precursor agent,catechol-o-methyltransferase inhibitors, ergoline dopamine agonists,ergot derivative/dopamine D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2B),5-HT_(2C), α_(2B) receptor agonists, antiparkinsonian agents,direct-acting skeletal muscle relaxants (hydantoin derivatives),noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zincsalts of gluconic acid, serotonin-1b and serotonin-1d receptoragonists/antimigraine agents, cytomegalovirus nucleoside analog DNApolymerase inhibitors and guanosine analogue antiviral agents.

Embodiments of the present invention include cocrystal compositions withTheanine dissolution of sumtriptan in combination with an NSAID.

Embodiments of the present invention include cocrystal compositions withTheanine dissolution of Levodopa in combination with Entacapone.

Embodiments of the present invention include cocrystal compositions withtheanine dissolution of zinc gluconate in combination with(R)-Ibuprofen.

Derivatives prepared using compositions according to embodiments of thepresent invention can be administered via intravenous, intramuscular,intradermal, transdermal, subcutaneous, intraperitoneal,intraventricular, intrathecal, intraarticular, sublingual,subconjunctival, and intravitreal routes, or in the form of eye drops,orally, topically, transmucosal, rectally, via nasal spray, inhalation,nanoparticle delivery systems, protein and peptide drug deliverysystems, beaded delivery systems, mucosal vaccine delivery, colloidaldrug carrier systems, controlled-released technology, liposomal andtargeted drug delivery systems, iontophoretic devices to administerdrugs through skin, programmable implanted drug-delivery devices,molecular targeting with immunoliposomes and other ligand-directedconstructs, drug carriers featuring direct molecular targeting of cancercells via antibody-mediated or other ligand-medicated interactions(Tiwari, G., “Drug Delivery Systems: An updated review.” Int J PharmIvestig. 2012 January-March; 2(1): 2-11).

The pharmaceutical compositions according to embodiments of the presentinvention may be prepared as oral solids (tablets, oral disintegratingtablets, effervescent tablets, capsules), oral liquids, hard or softgelatin capsules, microgels, microspheres, microcapsules, quickdissolve, controlled released, modified released, extended release, slowrelease, sustained release, syrups, suspensions, granules, wafer(films), pellets, lozenges, powders, chewable, suppositories, ointments,solutions, parenteral/injectable powders or granules that are pre-mixedor reconstituted, lotions, gels, creams, foams, propellants, strips,liposomes, proliposomes, prodrugs, cyclodextrins, m16 nasal and buccalaerosol sprays, encapsulated cells, oral soft gels, micellar solutions,vesicle and liquid crystal dispersions and nanoparticle dispersions(coated nanoparticles, pegylated nanoparticles, solid lipid particles,nanogels), and nanoemulsions (Tiwari, G., “Drug Delivery Systems: Anupdated review.” Int J Pharm Ivestig. 2012 January-March; 2(1): 2-11).

Cocrystals according to embodiments of the present invention may be usedto improve one or more physical properties, such as solubility,stability, and dissolution rate, of the active pharmaceutical ingredientof a selected treatment or prevention.

Next, the present invention will be described in further detail by meansof examples, without intending to limit the scope of the presentinvention to these examples alone. The following are exemplaryformulations with cocrystal compositions and Theanine dissolution fromthe following medication groups in accordance with the presentinvention: nucleoside analog reverse transcriptase inhibitors,non-nucleoside reverse transcriptase inhibitors, non-purine selectivexanthine oxidase inhibitors, leukotriene receptor antagonists,beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensiveagents, loop diuretics, thiazide diuretics, atypicalantipsychotic/partial dopamine agonists, non-steroidal anti-inflammatorydrugs, corticosteroids, antihistamines (ethanolamines, histamine H1receptor antagonists), antineoplastic agents (protein tyrosine kinaseinhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracyclinetopoisomerase inhibitors), antibacterial agents/antibiotics(cephalosporins, aminopenicillins, macrolides, sulfonamides,nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cycliclipopeptide antibiotics), antiviral agents, antifungal agents,antiprotozoan agents, immediate dopamine precursor agent,catechol-o-methyltransferase inhibitors, ergoline dopamine agonists,ergot derivative/dopamine D₂, D₃, D₄, 5-HT_(1A), 5-HT_(2A), 5-HT_(2B),5-HT_(2C), α_(2B) receptor agonists, antiparkinsonian agents,direct-acting skeletal muscle relaxants (hydantoin derivatives),noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zincsalts of gluconic acid, serotonin-1b and serotonin-1 d receptoragonists/antimigraine agents, cytomegalovirus nucleoside analog DNApolymerase inhibitors and guanosine analogue antiviral agents.

Experimental Details

X-ray powder diffraction (XRPD) patterns were obtained using a RigakuMiniFlex powder diffraction system, equipped with a horizontalgoniometer operating in the θ/2θ mode. The X-ray source wasnickel-filtered Kα emission of copper (1.54184 Å). Samples were packedinto the sample holder using a back-fill procedure, and were scannedover the range of 3.5 to 40 degrees 2θ at a scan rate of 0.5 degrees2θ/min. Using a data acquisition rate of 1 point per second, thesescanning parameters equate to a step size of 0.0084 degrees 2θ.Calibration of the diffractometer system was effected using purifiedtalc as a reference material. The intensity scale for all diffractionpatterns was normalized so that the relative intensity of the mostintense peak in the pattern equaled 100%.

Measurements of differential scanning calorimetry (DSC) were obtained ona TA Instruments 2910 thermal analysis system. Samples of approximately1-2 mg were accurately weighed into an aluminum DSC pan, and thencovered with an aluminum lid that was inverted and pressed down so as totightly contain the powder between the top and bottom aluminum faces ofthe lid and pan. The samples were then heated over the temperature rangeof 20-250° C., at a heating rate of 10° C./min.

Fourier-transform infrared absorption (FTIR) spectra were obtained at aresolution of 4 cm⁻¹ using a Shimadzu model 8400S spectrometer, witheach spectrum being obtained as the average of 40 individual spectra.The data were acquired using the attenuated total reflectance (ATR)sampling mode, where the samples were clamped against the ZnSe/diamondcrystal of a Pike MIRacle™ single reflection horizontal ATR samplingaccessory. The intensity scale for all spectra was normalized so thatthe relative intensity of the most intense peak in the spectrum 100%.

Example 1

0.327 g of amoxicillin trihydrate (0.780 mmol) and 0.136 g of L-theanine(0.781 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 1a , while the FTIR spectrum is shown inFIG. 1b . The DSC melting endotherm of the product was characterized bya peak maximum at 208° C.

Example 2

0.311 g of ampicillin trihydrate (0.771 mmol) and 0.141 g of L-theanine(0.809 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 2a , while the FTIR spectrum is shown inFIG. 2b . The DSC melting endotherm of the product was characterized bya peak maximum at 212° C.

Example 3

0.315 g of aripiprazole (0.703 mmol) and 0.129 g of L-theanine (0.741mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 3a , while the FTIR spectrum is shown in FIG. 3b . The DSC meltingendotherm of the product was characterized by a peak maximum at 148° C.

Example 4

0.165 g of bromocriptine (0.252 mmol) and 0.046 g of L-theanine (0.264mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 4a , while the FTIR spectrum is shown in FIG. 4b . The DSC meltingendotherm of the product was characterized by a peak maximum at 197° C.

Example 5

0.218 g of cabergoline (0.483 mmol) and 0.088 g of L-theanine (0.505mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 5a , while the FTIR spectrum is shown in FIG. 5b . The DSC meltingendotherm of the product was characterized by a peak maximum at 52° C.

Example 6

0.314 of cefadroxil monohydrate (0.849 mmol) and 0.151 g of L-theanine(0.867 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 6a , while the FTIR spectrum is shown inFIG. 6b . The DSC melting endotherm of the product was characterized bya peak maximum at 213° C.

Example 7

0.335 of cefdinir monohydrate (0.810 mmol) and 0.140 g of L-theanine(0.804 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 7a , while the FTIR spectrum is shown inFIG. 7b . The DSC melting endotherm of the product was characterized bya peak maximum at 157° C.

Example 8

0.208 g of cabergoline (0.662 mmol) and 0.115 g of L-theanine (0.660mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 8a , while the FTIR spectrum is shown in FIG. 8b . The DSC meltingendotherm of the product was characterized by a peak maximum at 209° C.

Example 9

0.256 g of daptomycin (0.158 mmol) and 0.030 g of L-theanine (0.172mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 9a , while the FTIR spectrum is shown in FIG. 9b . The DSC meltingendotherm of the product was characterized by a peak maximum at 213° C.

Example 10

0.373 g of diflunisal (1.491 mmol) and 0.269 g of L-theanine (1.544mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 10a , while the FTIR spectrum is shown in FIG. 10b . The DSCmelting endotherm of the product was characterized by a peak maximum at172° C.

Example 11

0.077 g of doxorubicin (0.142 mmol) and 0.027 g of L-theanine (0.155mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 11a , while the FTIR spectrum is shown in FIG. 11b . The DSCmelting endotherm of the product was characterized by a peak maximum at209° C.

Example 12

0.315 g of efavirenz (0.998 mmol) and 0.177 g of L-theanine (1.016 mmol)were weighed directly into the bowl of an agate mortar, and wetted with70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 12a , while the FTIR spectrum is shown in FIG. 12b . The DSCmelting endotherm of the product was characterized by a peak maximum at136° C.

Example 13

0.227 g of entacapone (0.744 mmol) and 0.132 g of L-theanine (0.758mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 13a , while the FTIR spectrum is shown in FIG. 13b . The DSCmelting endotherm of the product was characterized by a peak maximum at160° C.

Example 14

0.316 g of epinephrine (1.725 mmol) and 0.305 g of L-theanine (1.751mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 14a , while the FTIR spectrum is shown in FIG. 14b . The DSCmelting endotherm of the product was characterized by a peak maximum at205° C.

Example 15

0.417 g of erythromycin (0.568 mmol) and 0.101 g of L-theanine (0.580mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 15a , while the FTIR spectrum is shown in FIG. 15b . The DSCmelting endotherm of the product was characterized by a peak maximum at219° C.

Example 16

0.326 g of febuxostat (1.030 mmol) and 0.180 g of L-theanine (1.033mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 16a , while the FTIR spectrum is shown in FIG. 16b . The DSCmelting endotherm of the product was characterized by a peak maximum at182° C.

Example 17

0.330 g of fexofenadine (0.658 mmol) and 0.119 g of L-theanine (0.683mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 17a , while the FTIR spectrum is shown in FIG. 17b . The DSCmelting endotherm of the product was characterized by a peak maximum at206° C.

Example 18

0.355 g of fluconazole (1.159 mmol) and 0.204 g of L-theanine (1.171mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 18a , while the FTIR spectrum is shown in FIG. 18b . The DSCmelting endotherm of the product was characterized by a peak maximum at102° C.

Example 19

0.181 g of furosemide (0.547 mmol) and 0.094 g of L-theanine (0.540mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 19a , while the FTIR spectrum is shown in FIG. 19b . The DSCmelting endotherm of the product was characterized by a peak maximum at193° C.

Example 20

0.408 g of hydrochlorothiazide (1.370 mmol) and 0.239 g of L-theanine(1.372 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 20a , while the FTIR spectrum is shown inFIG. 20 b. The DSC melting endotherm of the product was characterized bya peak maximum at 204° C.

Example 21

0.246 g of R-ibuprofen (1.193 mmol) and 0.213 g of L-theanine (1.223mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 21a , while the FTIR spectrum is shown in FIG. 21b . The DSCmelting endotherm of the product was characterized by a peak maximum at51° C.

Example 22

0.309 g of irinotecan (0.527 mmol) and 0.094 g of L-theanine (0.540mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 22a , while the FTIR spectrum is shown in FIG. 22b . The DSCmelting endotherm of the product was characterized by a peak maximum at218° C.

Example 23

0.215 g of levodopa (1.090 mmol) and 0.191 g of L-theanine (1.096 mmol)were weighed directly into the bowl of an agate mortar, and wetted with70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 23a , while the FTIR spectrum is shown in FIG. 23b . The DSCmelting endotherm of the product was characterized by a peak maximum at211° C.

Example 24

0.142 g of memantine (0.792 mmol) and 0.140 g of L-theanine (0.804 mmol)were weighed directly into the bowl of an agate mortar, and wetted with70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 24a , while the FTIR spectrum is shown in FIG. 24b . The DSCmelting endotherm of the product was characterized by a peak maximum at207° C.

Example 25

0.335 g of metronidazole (1.957 mmol) and 0.348 g of L-theanine (1.998mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 25a , while the FTIR spectrum is shown in FIG. 25b . The DSCmelting endotherm of the product was characterized by a peak maximum at160° C.

Example 26

0.271 g of nilotinib (0.512 mmol) and 0.090 g of L-theanine (0.517 mmol)were weighed directly into the bowl of an agate mortar, and wetted with70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 26a , while the FTIR spectrum is shown in FIG. 26b . The DSCmelting endotherm of the product was characterized by a peak maximum at211° C.

Example 27

0.206 g of prednisone (0.575 mmol) and 0.103 g of L-theanine (0.591mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 27a , while the FTIR spectrum is shown in FIG. 27b . The DSCmelting endotherm of the product was characterized by a peak maximum at201° C.

Example 28

0.368 g of sulfamethoxazole (1.453 mmol) and 0.259 g of L-theanine(1.487 mmol) were weighed directly into the bowl of an agate mortar, andwetted with 70% isopropanol to form a moderately thick slurry. Theslurry was thoroughly ground at the time of mixing, and thenperiodically re-ground until the contents were dry. The XRPD pattern ofthe product is shown in FIG. 28a , while the FTIR spectrum is shown inFIG. 28b . The DSC melting endotherm of the product was characterized bya peak maximum at 169° C.

Example 29

0.425 g of sumitriptan (0.963 mmol) and 0.168 g of L-theanine (0.964mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 29a , while the FTIR spectrum is shown in FIG. 29b . The DSCmelting endotherm of the product was characterized by a peak maximum at173° C.

Example 30

0.348 g of valganciclovir (0.982 mmol) and 0.174 g of L-theanine (0.999mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 30a , while the FTIR spectrum is shown in FIG. 30b . The DSCmelting endotherm of the product was characterized by a peak maximum at212° C.

Example 31

0.397 g of zafirlukast (0.690 mmol) and 0.122 g of L-theanine (0.700mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 31a , while the FTIR spectrum is shown in FIG. 31b . The DSCmelting endotherm of the product was characterized by a peak maximum at211° C.

Example 32

0.343 g of zidovudine (1.283 mmol) and 0.226 g of L-theanine (1.297mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 32a , while the FTIR spectrum is shown in FIG. 32b . The DSCmelting endotherm of the product was characterized by a peak maximum at122° C.

Example 33

0.398 g of gluconate zinc (0.873 mmol) and 0.157 g of L-theanine (0.901mmol) were weighed directly into the bowl of an agate mortar, and wettedwith 70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 33a , while the FTIR spectrum is shown in FIG. 33b . The DSCmelting endotherm of the product was characterized by a peak maximum at164° C.

Example 34

0.384 g of Acyclovir (1.705 mmol) and 0.298 g of L-theanine (1.711 mmol)were weighed directly into the bowl of an agate mortar, and wetted with70% isopropanol to form a moderately thick slurry. The slurry wasthoroughly ground at the time of mixing, and then periodically re-grounduntil the contents were dry. The XRPD pattern of the product is shown inFIG. 34a , while the FTIR spectrum is shown in FIG. 34b . The DSCmelting endotherm of the product was characterized by a peak maximum at119° C.

Embodiments of the present invention include compositions of Theaninecombined with the drugs listed in the table below. Embodiments of thepresent invention employing crystallization and Theanine dissolution oflow solubility pharmaceuticals are highly-efficacious in the treatmentof a variety of emergent conditions where improved drug delivery wouldbenefit patients, including those presenting with, but not limited to,the conditions in the table below, with the drug(s) for treating thecondition(s) listed next to the condition(s):

Condition(s) Drug Acute pulmonary edema/congestive heart failure LasixAcute myocardial infarction Aspirin Acute ischemic stroke Aspirin Acuteallergic/anaphylactic reactions from medications, Epinephrine food,latex, insect bites/stings Cardiac arrest, acute exacerbation of asthma,ventricular Epinephrine fibrillation, airway obstruction Australian boxjelly fish envenomations Zinc gluconate Neurologic emergencies includingmalignant hyperthermia, Dantrolene ecstasyintoxication/3,4-methylenedioxymethamphetamine, sodium serotoninsyndrome, 2,4-dinitrophenol poisoning.

Embodiments of the present invention include compositions of Theaninecombined with the drugs listed in the table below. Embodiments of thepresent invention employing crystallization and Theanine dissolution oflow solubility pharmaceuticals are highly-efficacious in the treatmentof a variety of additional conditions where improved drug delivery wouldbenefit patients, including those presenting with, but not limited to,the conditions in the table below, with the drug(s) for treating thecondition(s) listed next to the condition(s):

Condition(s) Drug(s) Diseases/conditions associated with excessiveamounts of Theanine glutamate: Spinal cord injury, stroke, traumaticbrain injury, multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, alcoholism, alcohol withdrawal, over-rapid benzodiazepinewithdrawal, Huntington's disease, hypoglycemia, damage to a newbornsbrain caused by interrupted oxygen supply during delivery, exposure tonerve gas, and chronic nerve damage in such conditions as glaucoma,amyotrophic lateral sclerosis, and HIV dementia Parkinson's diseaseLevodopa, Entacapone, Nilotinib Hyperprolactinemia including amenorrheawith or without Bromocriptine galactorrhea, infertility or hypogonadism;prolactin-secreting adenomas, acromegaly, idiopathic or postencephaliticParkinson's disease Hyperprolactinemic disorders, either idiopathic ordue to Cabergoline pituitary adenomas Imatinib resistant chronicmyelogenous leukemia, Alzheimer's Nilotinib disease, Parkinson'sdisease, Huntington's disease, dementia, amyotrophic lateral sclerosisDiseases/conditions associated with: Excessive amounts of Memantineglutamate, including moderate to severe Alzheimer's diseaseNeurodegenerative diseases such as muscle spasticity Dantrolene sodiumassociated with multiple sclerosis, cerebral palsy, spinal cord injuryand cerebrovascular accidents Acute renal colic (R)-Ibuprofen, IVAspirin Acute pericarditis (R)-Ibuprofen, SL/IV aspirin Dental pain,ligament injuries, (R)-Ibuprofen, SL Aspirin HIV/AIDS Efavirenz,Zidovudine Clostridium difficile, trichomoniasis, bacterial infectionsof the Metronidazole vagina, acne rosacea, giardiasis, amoebiasis,abscess, surgical wound infections, helicobacter infections,pseudomembranous enterocolitis, bacteroides infections Cytomegalovirusretinitis in patients who have AIDS, AIDS Valganciclovir associatedopportunistic infections, prevents CMV disease in patients who havereceived an organ transplant Herpes simplex encephalitis, herpeslabialis (cold sores), Acyclovir genital herpes, varicella-zoster(shingles and chickenpox), acute mucocutaneous HSV infections inimmunocompromised patients, acute chickenpox in immunocompromisedpatients, ophthalmic herpes and herpes simplex blepharitis Oralcandida/fungal infections Fluconazole Listeriosis Ampicillin Bronchitis,diphtheria, Legionnaires disease, pertussis Erythromycin pneumonia,dental prophylaxis Uncomplicated urinary tract infections, pneumocystiscarinii Sulfamethoxzole pneumonia, toxoplasmosis, shigellosis,traveler's diarrhea Community-acquired pneumonia, acute exacerbations ofCefdinir chronic bronchitis, acute maxillary sinusitis, pharyngitis,tonsillitis, uncomplicated skin and soft tissue infections, acutebacterial otitis media Impetigo/soft tissue infections CefadroxilPharyngitis, tonsillitis, uncomplicated skin and soft tissue Amoxicillininfections, lower respiratory infections, early stage Lyme diseaseStaphylococcus aureus bacteremia including right sided Daptomycinendocarditis, complicated skin and skin structure gram-positivebacterial infections including MRSA Gout/hyperuricemia Febuxostat Heartfailure, hypertension, pulmonary edema, fluid retention Lasix (edema)associate with ascites, liver cirrhosis, nephrotic syndromeHypertension, heart failure, diabetes insipidus, fluid retentionHydrochlorothiazide (edema) in patients with congestive heart failure,cirrhosis of the liver, nephrotic syndrome in patients taking steroidsor estrogen Migraine, cluster headaches Sumatriptan, IV/SL AspirinRamsay Hunt Syndrome Acyclovir, Prednisone Inflammation, autoimmunediseases, Bell's palsy, Hashimoto's Prednisone, encephalopathy, skindiseases, mild to moderate allergies, asthma, COPD, chronic inflammatorydemyelinating polyneuropathy (CIDP), rheumatic disorders, allergicreactions, ulcerative colitis, Crohn's disease, adrenocorticalinsufficiency, thyroiditis, laryngitis, sinusitis, mild to moderateurticaria (hives), recurrent pericarditis, multiple sclerosis, nephroticsyndrome, myasthenia gravis, poison oak exposure, acute lymphoblasticleukemia, Non-Hodgkin lymphomas, Hodgkin's lymphoma, multiple myelomaand other hormone-sensitive tumors in combination with other anticancerdrugs, uveitis, and sarcoidosis. Rhinovirus colds, Australian box jellyfish stings Zinc gluconate Acute lymphoblastic leukemia, acutemyelobastic leukemia, Doxorubicin Wilm's tumor, neuroblastoma, softtissue and bone sarcomas, ovarian carcinoma, transitional cell bladdercarcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease,malignant lymphoma, and bronchogenic carcinoma (small cell histologictype), and adjuvant therapy in women with evidence of axillary lymphnode involvement following resection of primary breast cancer Metastaticcarcinoma of the colon and rectum Irinotecan Parkinson's disease anddopamine-responsive dystonias Levodopa Schizophrenia, bipolar disorder,autism Aripiprazole Pain, inflammation Diflunisal, (R)-Ibuprofen AsthmaZafirulkast, Prednisone, Hay fever Fexofenadine Stabilization ofbimembrane structures Zinc Gluconate (R)-Ibuprofen

While a specific embodiment of the invention has been shown anddescribed in detail to illustrate the application of the principles ofthe invention, it will be understood that the invention may be embodiedotherwise without departing from such principles.

What is claimed is:
 1. A method of making a water-solubledoxorubicin-theanine cocrystal composition comprising the steps of:providing a quantity of doxorubicin; adding a quantity of a theanineenantiomer to said quantity of doxorubicin to form a mixture comprisingsaid quantity of doxorubicin and said enantiomer of theanine; wettingsaid mixture; and grinding said mixture for a length of time sufficientto produce a dried crystalline mass.
 2. The method of claim 1, whereinsaid quantity of doxorubicin is approximately 0.077 g.
 3. The method ofclaim 1, wherein said quantity of theanine enantiomer is approximately0.027 g.
 4. The method of claim 1, wherein said quantity of doxorubicinis approximately 75% by weight of said mixture of said quantity ofdoxorubicin and said enantiomer of theanine.
 5. The method of claim 1,wherein said quantity of theanine enantiomer is approximately 25% byweight of said mixture of said quantity of doxorubicin and saidenantiomer of theanine.
 6. The method of claim 1, wherein said theanineenantiomer is selected from the group consisting of L-theanine,D-theanine, and DL-theanine.
 7. The method of claim 1, wherein saidtheanine enantiomer is selected from the group consisting of alphavariant of theanine and a beta variant of theanine.
 8. The method ofclaim 7, wherein said alpha variant of theanine is selected from thegroup consisting of L-homotheanine, D-homotheanine, DL-homotheanine,L-bishomotheanine, D-bishomotheanine, and DL-bishomotheanine.
 9. Themethod of claim 7, wherein said alpha variant of theanine is ahomologous analog of theanine.
 10. The method of claim 7, wherein saidalpha variant of theanine contains a functional group selected from thegroup consisting of linear, cyclic, or branched alkyl and derivativesthereof; linear, cyclic, or branched alkenyl and derivatives thereof;and aromatic radicals and derivatives thereof.
 11. The method of claim10, wherein said aromatic radicals are aryl radicals.
 12. The method ofclaim 1, wherein said theanine enantiomer is a racemic mixture of a betavariant of theanine containing a functional group selected from thegroup consisting of linear, cyclic, or branched alkyl groups andderivatives thereof; linear, cyclic, or branched alkenyl groups andderivatives thereof; and aromatic radicals and derivatives thereof. 13.The method of claim 12, wherein said aromatic radicals are arylradicals.
 14. The method claim 1, wherein said theanine enantiomer is anS enantiomer of a beta variant of theanine containing a functional groupselected from the group consisting of linear, cyclic, or branched alkylgroups and derivatives thereof; linear, cyclic, or branched alkenylgroups and derivatives thereof; and aromatic radicals and derivativesthereof.
 15. The method of claim 14, wherein said aromatic radicals arearyl radicals.
 16. The method of claim 1, wherein said theanineenantiomer is an R enantiomer of a beta variant of theanine containing afunctional group selected from the group consisting of linear, cyclic,or branched alkyl groups and derivatives thereof; linear, cyclic, orbranched alkenyl groups and derivatives thereof; and aromatic radicalsand derivatives thereof.
 17. The method of claim 16, wherein saidaromatic radicals are aryl radicals.
 18. The method of claim 1, furthercomprising adding a sugar alcohol to said mixture.
 19. The method ofclaim 18, wherein said sugar alcohol has a configuration selected fromthe group consisting of the L-configuration and the D-configuration. 20.The method of claim 1, wherein said theanine enantiomer is selected fromthe group consisting of an L-enantiomer of the alpha variant oftheanine, a D-enantiomer of the alpha variant of theanine, aDL-enantiomer of the alpha variant of theanine, an L-isomer of the alphavariant of theanine, a D-isomer of the alpha variant of theanine, aDL-racemic mixture of the alpha variant of theanine, an S-isomer of thealpha variant of theanine, an R-isomer of the alpha variant of theanine,an S,R-racemic mixture of the alpha variant of theanine, rotamers of thealpha variant of theanine, tautomers of the alpha variant of theanine,salt forms of the alpha variant of theanine, hydrates of the alphavariant of theanine, an L-enantiomer of the beta variant of theanine, aD-enantiomer of the beta variant of theanine, a DL-enantiomer of thebeta variant of theanine, an L-isomer of the beta variant of theanine, aD-isomer of the beta variant of theanine, a DL-racemic mixture of thebeta variant of theanine, an S-isomer of the beta variant of theanine,an R-isomer of the beta variant of theanine, an S,R-racemic mixture ofthe beta variant of theanine, rotamers of the beta variant of theanine,tautomers of the beta variant of theanine, salt forms of the betavariant of theanine, and hydrates of the beta variant of theanine. 21.The method of claim 1, wherein said theanine enantiomer is selected fromthe group consisting of L-theanine, D-theanine, and DL-theanine.
 22. Themethod of claim 1, wherein 70% isopropanol is employed in said wettingstep.
 23. The method of claim 1, wherein the theanine enantiomer isselected from the group consisting of L-alpha amino acids of theanine,D-alpha amino acids of theanine, and DL-alpha amino acids of theanineand wherein the theanine enantiomer further comprises a side-chaincarbon homologue selected from the group consisting of nor-homologues,homo-homologues, and bis-homologues.